Genital herpes is one of the most prevalent sexually transmitted infections worldwide and is associated with substantial morbidity. The impact of genital herpes as a public health threat is amplified because of its epidemiologic synergy with HIV. Epidemiological studies consistently demonstrate that HSV infection increases the risk of HIV transmission and acquisition. The increasing prevalence of primary HSV infection, clinical recurrences and high rates of silent reactivation fuel the spread of both HSV and HIV and highlight the urgent need for novel prevention strategies. HSV vaccine development has been elusive, however, the most promising results were obtained in two trials with a HSV-2 glycoprotein D (gD) subunit vaccine developed by GlaxoSmithKline (GSK) in which the vaccine provided partial protection for women who were seronegative for both HSV-1 and HSV-2 at baseline, but failed to protect men or to protect HSV-1 seropositive women. To address the limitations and inadequacies of the current models, we established female (vaginal) and male (disrupted penile skin) cotton rat models of genital herpes. We have also established models of oral and ocular HSV- 1 infection, thus providing the opportunity to compare vaccine responses in HSV-1 seropositive and HSV-1 naive animals. Additional advantages of the cotton rat include the availability of reagents to study humoral and cellular mucosal and systemic immune responses. The overall goal of this Phase I STTR is to determine if the cotton rat provides a model predictive of clinical responses to vaccines by comparing the efficacy of the GSK gD subunit vaccine in male and female cotton rats. We hypothesize that the vaccine will provide greater protection in HSV-naive females compared to males and in HSV-1 naove compared to HSV-1 seropositive females, thus recapitulating what happened in the human clinical trials. We will compare the impact of the vaccine on primary infection and disease, rates of clinical and subclinical recurrences, and mucosal and systemic humoral and cellular immune responses. Results obtained will provide insights into the mechanisms underlying gender specific responses and establish the framework for future studies to evaluate next generation vaccines as well as other prevention strategies. PUBLIC HEALTH RELEVANCE: Genital herpes is one of the most prevalent sexually transmitted infections worldwide and is associated with substantial morbidity. Epidemiological studies consistently demonstrate that HSV infection increases the risk of HIV transmission and acquisition. HSV vaccine development has been elusive, however, the most promising results were obtained in two trials with a glycoprotein D (gD) subunit vaccine developed by GlaxoSmithKline (GSK) in which the vaccine provided partial protection for women who were seronegative for both HSV-1 and HSV-2 at baseline, but failed to protect men or to protect HSV-1 seropositive women. To address the limitations and inadequacies of the current models, we established female (vaginal) and male (disrupted penile skin) cotton rat models of genital herpes. The goal of Phase 1 of this STTR application is to compare the efficacy of the GSK gD-2-Alum monophosphoryl lipid A (MPL) vaccine in female and male cotton rats.